Academic Commons Search Resultshttps://academiccommons.columbia.edu/catalog?action=index&controller=catalog&f%5Bdepartment_facet%5D%5B%5D=Medicine&f%5Bsubject_facet%5D%5B%5D=Physiology&format=rss&fq%5B%5D=has_model_ssim%3A%22info%3Afedora%2Fldpd%3AContentAggregator%22&q=&rows=500&sort=record_creation_date+desc
Academic Commons Search Resultsen-usEndothelial cell cytosolic free calcium regulates neutrophil migration across monolayers of endothelial cellshttps://academiccommons.columbia.edu/catalog/ac:192958
Huang, Ada J.; Manning, John E.; Bandak, Tania M.; Ratau, Michelle C.; Hanser, Katharine R.; Silverstein, Samuel C.http://dx.doi.org/10.7916/D8RB74CJWed, 13 Jan 2016 16:34:26 +0000Polymorphonuclear leukocytes (PMN) traverse an endothelial cell (EC) barrier by crawling between neighboring EC. Whether EC regulate the integrity of their intercellular adhesive and junctional contacts in response to chemotaxing PMN is unresolved. EC respond to the binding of soluble mediators such as histamine by increasing their cytosolic free calcium concentration ([Ca++]i) (Rotrosen, D., and J.I. Gallin. 1986. J. Cell Biol. 103:2379-2387) and undergoing shape changes (Majno, G., S. M. Shea, and M. Leventhal. 1969. J. Cell Biol. 42:617-672). Substances such as leukotriene C4 (LTC4) and thrombin, which increased the permeability of EC monolayers to ions, as measured by the electrical resistance of the monolayers, transiently increased EC [Ca++]i. To determine whether chemotaxing PMN cause similar changes in EC [Ca++]i, human umbilical vein endothelial cells (HUVEC) maintained as monolayers were loaded with fura-2. [Ca++]i was measured in single EC during PMN adhesion to and migration across these monolayers. PMN-EC adhesion and transendothelial PMN migration in response to formyl-methionyl-leucyl-phenylalanine (fMLP) as well as to interleukin 1 (IL-1) treated EC induced a transient increase in EC [Ca++]i which temporally corresponded with the time course of PMN-EC interactions. When EC [Ca++]i was clamped at resting levels with a cell permeant calcium buffer, PMN migration across EC monolayers and PMN induced changes in EC monolayer permeability were inhibited. However, clamping of EC [Ca++]i did not inhibit PMN-EC adhesion. These studies provide evidence that EC respond to stimulated PMN by increasing their [Ca++]i and that this increase in [Ca++]i causes an increase in EC monolayer permeability. Such [Ca++]i increases are required for PMN transit across an EC barrier. We suggest EC [Ca++]i regulates transendothelial migration of PMN by participating in a signal cascade which stimulates EC to open their intercellular junctions to allow transendothelial passage of leukocytes.Cellular biology, Microbiology, Physiology, Neutrophils, Endothelial cells, Membranes (Biology)--Permeability, Calcium ions--Physiological effectscs3Medicine, Physiology and Cellular BiophysicsArticlesLipoprotein lipase regulates Fc receptor-mediated phagocytosis by macrophages maintained in glucose-deficient mediumhttps://academiccommons.columbia.edu/catalog/ac:192955
Yin, Baoyun; Loike, John D.; Kako, Yuko; Weinstock, Peter H.; Breslow, Jan L.; Silverstein, Samuel C.; Goldberg, Ira Jayhttp://dx.doi.org/10.7916/D80R9P5JTue, 12 Jan 2016 19:35:45 +0000During periods of intense activity such as phagocytosis, macrophages are thought to derive most of their energy from glucose metabolism under both aerobic and anaerobic conditions. To determine whether fatty acids released from lipoproteins by macrophage lipoprotein lipase (LPL) could substitute for glucose as a source of energy for phagocytosis, we cultured peritoneal macrophages from normal and LPL knockout (LPL-KO) mice that had been rescued from neonatal demise by expression of human LPL via the muscle creatine kinase promoter. Normal and LPL-KO macrophages were cultured in medium containing normal (5 mM) or low (1 mM) glucose, and were tested for their capacity to phagocytose IgG-opsonized sheep erythrocytes. LPL-KO macrophages maintained in 1 and 5 mM glucose phagocytosed 67 and 79% fewer IgG-opsonized erythrocytes, respectively, than macrophages from normal mice. Addition of VLDL to LPL-expressing macrophages maintained in 1 mM glucose enhanced the macrophages' phagocytosis of IgG-opsonized erythrocytes, but did not stimulate phagocytosis by LPL-KO macrophages. Inhibition of secreted LPL with a monoclonal anti-LPL antibody or with tetrahydrolipstatin blocked the ability of VLDL to enhance phagocytosis by LPL-expressing macrophages maintained in 1 mM glucose. Addition of oleic acid significantly enhanced phagocytosis by both LPL-expressing and LPL-KO macrophages maintained in 1 mM glucose. Moreover, oleic acid stimulated phagocytosis in cells cultured in non-glucose-containing medium, and increased the intracellular stores of creatine phosphate. Inhibition of oxidative phosphorylation, but not of glycolysis, blocked the capacity of oleic acid to stimulate phagocytosis. Receptor-mediated endocytosis of acetyl LDL by macrophages from LPL-expressing and LPL-KO mice was similar whether the cells were maintained in 5 or 1 mM glucose, and was not augmented by VLDL. We postulate that fatty acids derived from macrophage LPL-catalyzed hydrolysis of triglycerides and phospholipids provide energy for macrophages in areas that have limited amounts of ambient glucose, and during periods of intense metabolic activity.Cellular biology, Microbiology, Physiology, Lipoprotein lipase, Macrophages, Atherosclerosis, Glucosejdl5, scs3, ijg3Medicine, Physiology and Cellular BiophysicsArticlesBody circumferences: clinical implications emerging from a new geometric modelhttps://academiccommons.columbia.edu/catalog/ac:197753
Heymsfield, Steven B.; Martin-Nguyen, Allison; Fong, Tung; Gallagher, Dympna; Pietrobelli, Angelohttp://dx.doi.org/10.7916/D8FT8JJ5Tue, 09 Sep 2014 16:32:28 +0000Background: Body volume expands with the positive energy balance associated with the development of adult human obesity and this "growth" is captured by two widely used clinical metrics, waist circumference and body mass index (BMI). Empirical correlations between circumferences, BMI, and related body compartments are frequently reported but fail to provide an important common conceptual foundation that can be related to key clinical observations. A two-phase program was designed to fill this important gap: a geometric model linking body volume with circumferences and BMI was developed and validated in cross-sectional cohorts; and the model was applied to the evaluation of longitudinally monitored subjects during periods of voluntary weight loss. Concepts emerging from the developed model were then used to examine the relations between the evaluated clinical measures and body composition. Methods: Two groups of healthy adults (n = 494 and 1499) were included in the cross-sectional model development/testing phase and subjects in two previous weight loss studies were included in the longitudinal model evaluation phase. Five circumferences (arm, waist, hip, thigh, and calf; average of sum, C), height (H), BMI, body volume (V; underwater weighing), and the volumes of major body compartments (whole-body magnetic resonance imaging) were measured. Results: The evaluation of a humanoid geometric model based a cylinder confirmed that V derived from C and H was highly correlated with measured V [R2 both males and females, 0.97; p < 0.001). Developed allometric models confirmed model predictions that C and BMI (represented as V/H) are directly linked as, C = (V/H)0.5. The scaling of individual circumferences to V/H varied, with waist the highest (V/H~0.6) and calf the lowest (V/H~0.3), indicating that the largest and smallest between-subject "growth" with greater body volume occurs in the abdominal area and lower extremities, respectively. A stepwise linear regression model including all five circumferences2 showed that each contributed independently to V/H. These cross-sectional observations were generally confirmed by analysis of the two longitudinal weight loss studies. The scaling of circumference ratios (e.g., waist/hip) to V/H conformed to models developed on the scaling of individual circumferences to V/H, indicating their relations to BMI are predictable a priori. Waist, hip, and arm/calf circumferences had the highest associations with whole-body visceral adipose tissue, subcutaneous adipose tissue, and skeletal muscle volumes, respectively. Conclusion: These observations provide a simple geometric model relating circumferences with body size and composition, introduce a conceptual foundation explaining previous empirical observations, and reveal new clinical insights.Health sciences, Physiology, Body mass index, Obesitysbh2, dg108MedicineArticlesMolecular and Physiological Adaptations to Weight Perturbation in Micehttps://academiccommons.columbia.edu/catalog/ac:139272
Ravussin, Yannhttp://hdl.handle.net/10022/AC:P:11289Wed, 28 Sep 2011 13:24:37 +0000From a medical perspective, obesity may be defined as a degree of relative adiposity sufficient to derange metabolic physiology in a manner that negatively impacts the health of the individual. While population-based cut points based on body mass index (BMI) are frequently used as a means of identifying such individuals, this is an imprecise approach since the critical levels of adiposity in this regard differ substantially among individuals. Our common genetic predisposition to increased adiposity, coupled with an environment conducive to positive energy balance results in an increasing prevalence of human obesity. Weight loss, even when initially successful, is very difficult to maintain due, in part, to a feedback system involving metabolic, behavioral, neuroendocrine and autonomic responses that are initiated to maintain somatic energy stores (fat) at a level considered `ideal' by the central nervous system (CNS). Circulating leptin is an important afferent signal to the CNS relating peripheral energy stores with modulations in key leptin sensing area sensitivity possibly implicated in the functional and molecular basis of defense of body weight. These physiological responses, which include increased metabolic efficiency at lower body weight, may be engaged in individuals at different levels of body fat depending on their genetic makeup, as well as on gestational and post-natal environmental factors that have determined the so-called "set-point". In the work presented in this dissertation the following aspects of the physiology of the defense of body weight were explored: 1) whether levels (thresholds) of defended adiposity can be raised or lowered by environmental manipulation; 2) the physiological and molecular changes that mediate increased metabolic efficiency following weight loss, 3) leptin's role in setting the threshold; 4) the effects of ambient temperature on metabolic phenotypes of weight perturbed to assess whether torpor contributes to metabolic adaptation; and 5) whether changes in gut microbiota accompany changes in diet composition and/or body weight. To assess whether the threshold for defended body weight could be increased or decreased by environmental manipulations (i.e. high fat diet and weight restriction), we identified bioenergetic, behavioral, and CNS structural responses of C57BL/6J in long term diet induced obese (DIO) male mice to weight reduction. We found that maintenance of a body weight 20% below that imposed by a high fat diet results in metabolic adaptation - energy expenditure below that expected for body mass and composition - and structural changes of synapses onto arcuate pro-opiomelanocortin (POMC) cell bodies. These changes are qualitatively and quantitatively similar to those observed in weight-reduced animals that were never obese, suggesting that the previously obese animals are now "defending" a higher body weight. Maintenance of a lower body weight for more than 3 months was not accompanied by remission of the increased metabolic efficiency. Thus, the consequence of long term elevation of body weight suggests an increase in defended body fat that does not abate with time. Mice can enter torpor - a state of decreased metabolic rate and concomitant decrease in body temperature - as a defense mechanism in times of low caloric availability and/or decreased ambient room temperatures. Declines in circulating leptin concentrations and low ambient room temperature have both been implicated in the onset of torpor. To assess the effects of ambient room temperature and leptin concentrations on metabolic adaptation, we characterized C57BL/6J and leptin deficient (Lepob) mice following weight perturbation at both 22°C and 30°C ambients. Weight-reduced C57BL/6J mice show metabolic adaptation at both ambient temperatures and do not enter torpor whereas weight-reduced Lepob animals readily enter torpor at 22°C. This suggests that sufficiently high absolute leptin concentrations may impede the onset of torpor and that torpor itself does not contribute to metabolic adaptation in mice that have an intact leptin axis. To assess whether hyperleptinemia per se was capable of increasing the threshold for defended body weight, leptin was infused by minipumps into C57BL/6J mice for 18 weeks and body weight and metabolic parameters were studied following cessation of leptin infusion. Leptin infused mice did not defend elevated body weights compared to PBS infused mice suggesting that leptin alone may not be capable of setting the threshold for body weight defense implying that other changes accompanying obesity (i.e. increased free fatty acids, endoplasmic reticulum stress and/or inflammation of leptin-sensitive neural areas) are implicated. A caveat and possible confound to this study is the possibility of antibody production against the exogenous leptin that could have drastically decreased the amount of bioavailable leptin in these mice. This experiment did not assess antibody production but subsequent studies should do so. Finally, gut microbiota have been implicated in the regulation of body weight possibly by impacting insulin resistance, inflammation, and adiposity via interactions with epithelial and endocrine cells. We assessed changes in relative abundances of cecal microbiota in mice following sustained changes in body weight and diet composition. In diet-induced obese (DIO) mice, we find that weight reduction resulted in shifts in specific bacteria abundance (Akkermansia and Mucispirillum) and that these changes were correlated with leptin concentrations. Leptin modulates mucin production in the gut possibly altering local microniches for certain bacteria providing a functional link between adiposity and gut-specific changes in bacterial populations. Overall, the major findings of these experiments are that the threshold for body weight defense can be raised but not lowered, that metabolic adaptation observed in weight-reduced mice is not a result of torpor, and that hyperleptinemia (if no anti-bodies were produced) per se isolated from other obesity-related changes does not appear capable of raising the threshold.Physiologyyr2154Cellular, Molecular, Structural, and Genetic Studies, Pediatrics, MedicineDissertations